Mucosal-associated lymphoid tissues are the immune structures that rapidly initiate local immune responses; the dura mater is the outermost layer of the meninges covering and connecting central nervous system (CNS) with the periphery. In a recent work published in Nature, Fitzpatrick et al. demonstrate the presence of dura-associated lymphoid tissue, which forms during early postnatal development and expands following infections to protect the fenestrated dural vasculature and prevent pathogen entry into the CNS.

The central nervous system (CNS) is protected by several barriers that prevent invasion of pathogens and regulate immune responses. For example, the blood-brain barrier (BBB) restricts molecular and cellular entrance into the parenchyma from blood vessels. The meninges that cover CNS also serve as a barrier. The dura mater is the outermost layer of the meninges and unlike the other brain border compartments, contains all the features required to mount immune responses. These include bona fide lymphatic vasculature,1 blood vasculature that permits homeostatic immune trafficking, and a rich diversity of resident immune cells.2 Furthermore, the dura has access to both CNS antigens, through cerebrospinal fluid (CSF) efflux, as well as peripheral antigens through the fenestrated vasculature. However, the fenestrated vasculature also makes the dura mater susceptible to infection. Furthermore, the dural venous sinuses are adjacent to gaps in the arachnoid, known as arachnoid cuff exit (ACE) points, which may enable the spread of infections from the dura to the CNS.3

Mucosal barrier tissues present in gut, skin and other organs are among the body’s first line of defense due to constant and direct contact with foreign agents. Besides lymph nodes and spleen, mucosa-associated lymphoid tissues (MALTs) such as Peyer’s patches and nasal/nasopharynx-associated lymphoid tissues (NALTs) are secondary lymphoid organs (SLOs) that are critical for initiating and shaping local immune responses.4 While most SLOs form in predetermined locations and generally comprise of T cells, B cells, antigen presenting cells, stromal cells and integrate with blood and lymphatic vasculatures, the composition of MALT such as the Bronchus-associated lymphoid tissue (BALT) and NALT could be plastic and prone to continuous reshaping owing to constant antigen exposure.5

Fitzpatrick et al.6 demonstrated the presence of a lymphoid tissue — the rostral-rhinal venolymphatic hub, with an analogous structure to MALT, which is housed at the rostral-rhinal confluence of sinuses and associated with the dura mater. They initially noticed that there were large clusters of CD45-positve immune cells around the dural venous sinuses, and when examined in more detail they were to be bona fide germinal centers containing proliferating B cells, Tfh, and plasma cells.6 The most prominent of these is found near the rostral confluence of sinuses. Surprisingly, germinal centers were present in the dura, even in healthy mice, with a unique B cell receptor (BCR) repertoire suggesting local expansion of B cells (Fig. 1). This rostral-rhinal venolymphatic hub is interconnected with lymphatic vessels and fenestrated veins including the olfactory sinus, diploic veins, rostral-rhinal sinus, superior sagittal sinus, and bridging veins. Being so close to the nose, the authors speculated that this site may be particularly exposed to intranasal pathogens and indeed when viruses are infected intranasally, antigen-specific immune cells are recruited to dura-associated lymphoid tissue (DALT) to protect brain from the virus through humoral immunity. Besides the proximity, the connections of this lymphoid tissue to the olfactory bulbs via rostral-rhinal sinuses and cortical veins leads us to wonder whether and how this hub interplays with the NALT and the associated lymphatics in response to antigenic challenges.

Fig. 1: Identification of DALT.
figure 1

Immune cell aggregates, DALTs, are located along with sinuses. The largest structure was located at the rostral-rhinal venolymphatic hub. This structure is surrounded by fenestrated blood vessels and lymphatic vessels. Antigen or pathogen exposure initiates local immune response from the DALT. DALT contributes to the prevention of pathogen entry to the CNS. TS transverse sinus; SSS superior sagittal sinus. Created with BioRender.com.

Interestingly, the rostral-rhinal venolymphatic hub is present in early postnatal animals, from P8/9, but expands greatly during aging. It would be interesting to determine the developmental dynamics of DALT and its relationship with the microbiome. Indeed, it is tempting to speculate that, like MALT, it expands greatly during the early postnatal period probably upon exposure to the microbiome but is likely more sensitive to nasal colonization. Furthermore, although the focus of this study was the response to peripheral pathogens, DALT also may have access to CNS antigens through CSF efflux to the dura. It would be interesting to examine these structures in the context of autoimmune neuroinflammation. DALT could even provide a mechanistic link between peripheral infections, such as Epstein-Barr Virus, and autoimmune diseases of the CNS, such as multiple sclerosis.7,8

This study highlights the critical role of the dura as an immunological barrier for the CNS.9 This is likely necessary because of the presence of ACE points, effectively weak spots in the CNS barrier system that may enable the entry of pathogens to the CNS. Indeed, antigen presentation by dural immune cells is essential to control CNS infections, and the rich immunological diversity in the dura is likely directed towards protecting these ACE points.

This study showed presence of a lymphoid tissue associated with the dura under homeostasis and characterized detailed immune responses to infection. There are many open questions remaining. For example, the mechanisms that govern DALT formation and responses of DALT (structure and function) under different neurological and psychiatric disease conditions, in addition to neuroinflammatory and infectious conditions. Because each MALT has distinct characteristics due to unique anatomy and location, characterization of DALT compared to other MALTs would also be important. It will also be interesting to determine the relationship of DALT with CNS aging, and what the consequences of targeting DALT are on brain function and aging.